Ph- Adrenal Steroids Flashcards
What are the 3 layers of the adrenal cortex?
What is synthesized in each layer?
What is the regulation for each layer?
Zona glomerulosa -
- synthesis of mineralocorticoids [aldo]
- regulated by Ang II/ K+
- stimulated ACUTELY by ACTH
Zona Fasciculata
- synthesis of glucocorticoids [cortisol]
- regulated by ACTH and HP axis
Zona Reticularis
- synthesis of androgens [DHEA-S, androstenedione]
- regulated by ACTH and HP axis
When the HP axis fails, what layers of the adrenal gland will atrophy?
ZF and ZR
What are the 5 carbon changes of cholesterol that can be altered to synthesize cortisol, aldosterone and androgens?
19, 11, 18, 17, 21
What is the rate limiting step in the synthesis of steroids from cholesterol?
Cholesterol side chain is cleaved by StAR enzyme between carbons 20 and 22 to yield pregnenolone.
How does ACTH acutely stimulate aldosterone production?
ACTH binds to cells in the adrenal and increase cAMP which controls the flux or cholesterol into the mitochondria for scc.
What 2 factors the hypothalamus to secrete CRH?
What is the inhibitory factor?
Stimulation:
- Diurnal rhythm - highest levels at 8am
- Stess cytokines -increase steroidogensis 10x
Inhibition-
1. glucocorticoids/adrenal corticosteroids via neg feedback
Which cell of the anterior pituitary is least likely to fail? What is the implication of this?
Corticotropes are least likely to fail, so if ACTH is deficient, you must assess the whole ant. pituitary [GH, TSH, LH/FSH]
What is the action of ACTH when it is released from the corticotropes in the ant. pituitary?
- it is liberated from the POMC precursor via proteolysis
- Binds to Gs receptor and activates adenylyl cyclase
- increases cAMP in the adrenals to
- stimulate conversion of cholesterol to pregnenolone by enhancing StAR gene to transport it from outer to inner mit. membrane
- increase cholesterol uptake into the mitochodria
- increasing p450 scc.
When is ACTH used therapeutically?
It is NOT used because all the known therapeutic effects of ACTH can be achieved with corticosteroids [with greater ease, lower cost]
It is used however to test the integrity of the HPA axis to identify the patients that need supplemental steroids
What is Cosyntropin used for?
Cosyntropin Stimulation test- it is basically an ACTH analog given by IV push and then cortisol is measured over 30-60 minutes.
Low Dose Cosyntropin test- diagnoses secondary adrenal insufficiency [because in the absence of chronic ACTH, the adrenal will have atrophied and there will be no corticosteroid production.]
High Dose Cosyntropin test - evaluates synthetic capacity of adrenal cortex and is needed to differentiate various enzymatic defects that cause primary adrenal insufficiency [CAH-21hydroxylase def]
How many carbons do glucocorticoids and mineralocorticoids have?
How many do androgens have?
Glucocorticoids and mineralocorticoids both have 21 carbons and are collectively called corticosteroids.
Androgens are C19 steroids
Why is DHEA-s useful as a clinical measure of adrenal function?
DHEAS is made EXCLUSIVELY in the adrenals so it is a good marker
What is the only adrenal product that can feed back on the ant. pituitary and hypothalamus to repress further ACTH release?’
In addition to repression of the axis, how else does this adrenal product inhibit sythesis of more steroids?
glucocorticoids directly inhibit hypothalamus and ant. pituitary.
In addition, they suppress the release of stress/inflammatory cytokines which suppresses the release of CRH
How is ACTH measured?
What are the 3 problems with the test?
What can give falsely low numbers?
Immunoassays are limited by:
- rapid fluctuation in plasma concentrations
- losses due to sample handling
- coexistence of peptide fragments
So “sandwich” assays are used with 2 antibodies to 2 different isotopes to measure biologically active ACTH.
False low values if it is ectopic ACTH because the fragments are too small to be detected by sandwich assay, but are still biologically active.
What is the ACTH level in primary and secondary hypoaldosteronism?
Primary has high ACTH
Secondary has low ACTH
How does measuring ACTH help you distinguish between ACTH-dependent and independent Cushing syndrome?
If ACTH is high, then it is ACTH dependent.
If ACTH is low, and cortisol is high, that means it is a primary problem
How are corticosteroids managed in circulation?
- over 90% of cortisol is reversibly bound to plasma proteins [90% CBG, 10% albumin]
- aldosterone is NOT bound
- glucocorticoids are inactivated in the liver
What is the effect of impaired liver function on corticosteroid concentratons?
Liver synthesizes albumin and CBG which carry cortisol. If there is less binding globulins, there will be more free cortisol
The liver ALSO inactivates glucocorticoids. This will also increase glucocorticoid concentrations.
There is no real effect on the mineralocorticoids
Describe RAAS regulation of aldosterone.
What is the limiting agent in this process?
- Renin is secreted by the JG cells of the macula densa of the kidney in response to low perfusion, hyponatremia, sympathetics.
- Renin converts angiotensinogen to Ang I in the liver.
- Ang I is converted to AngII by ACE in vascular endothelium.
- AngII binds receptors in ZG to stimulate aldo synthesis
Renin is the limiting agent and is useful as a clinical measure of volume status
What 2 factors will increase aldosterone synthesis?
What will inhibit aldosterone synthesis?
Stimulated by:
- Ang II, hyperkalemia via Ca2+
- ACTH via cAMP
Inhibited by:
1. hypertension, hypernatremia
Describe corticosteroid receptors.
- How do they exist when they are not bound?
- What family do they belong to?
- What is the process once the ligand binds?
- When do they activate transcription?
- When do they inhibit transcription?
- Prior to binding of the corticosteroid, the receptors are in the cytoplasm as a multi-protein complex made up of HSP70, HSP90 and immunophilins.
2, nuclear hormone receptor family
- Once the ligand binds, the receptor goes through a confirmational change, dissociates with the plasma proteins and goes to the nucleus where the ligand-receptor complex binds glucocorticoid response element [GRE] and initiate or inhibit transcription
- activation –> primary carbohydrate metabolism
- repression [when bound to Jun Fos]–> suppression of immune response
How long does it take to get a response in target tissue by corticosteroids?
Because protein synthesis needs to occur, this is not a rapid response. It takes about 30-60 minutes
What are the 2 corticosteroid receptors? What are their specificities?
GR - binds only glucocorticoids
MR- binds glucocorticoids AND mineralocorticoids. Excess glucocorticoids can lead to spillover effect
What usually prevents the binding of glucocorticoids to MR?
11b-HSD usually converts cortisol to cortisone which is unable to bind to the MR receptor
What are the 4 main ways mineralocorticoids affect salt and water balance?
- enhances free water excretion [GC and MCs]
- enhance Na reabsorption at the distal tubule
- increases Na/K ATPase activity
- manages K homeostasis
What is the effect of primary adrenal insufficiency on free water?
Primary adrenal insufficiency causes hyponatremia because free water is not being excreted effectively at the tubule
What is the effect of aldosterone on Na reabsorption?
What are the 3 ways it physiologically controls it?
Aldo:
- increases expression of ENaC - the rate limiting step for controlling Na flux
- increases SGK1 which activates ENaC
- increases Na/K ATPase activity in the basolateral membrane to enhance reabsorption** this is the main mechanism for enhancing Na reabsorption
How does aldosterone affect K homeostasis?
SGKT1 may activate ROMK to allow excretion of excess K.
If there is adrenal insufficiency, hyperkalemia may be a late finding.
If there is Conn sydrome, hypokalemia is a finding
What are the only places on the body where MR are found?
- Kidney- distal tubules, collecting ducts
- Sweat glands, salivary glands, exocrine pancreas, GI mucosa
- brain
In peripheral circulation, cortisol is 100x greater concentration than aldosterone.
What is an organ where MR is activated all the time by glucocorticoids?
What is an organ where MR is RARELY activated by glucocorticoid? Why?
Brain - MR is activated by GCs [maybe how GCs repress ACTH by feedback?]
Kidney- MR functions exclusively as aldo receptor because the kidney expresses 11B-HSD type 2 which converts cortisol to cortisone
What is apparent mineralocorticoid excess [AME]?
When there is a mutation in 11b-HSD2 allowing normal circulation levels of GCs to superactivate MR in the kidney —>hypertension and hypokalemia
What are the 3 hormones that are activated when glucose is low?
- Epi is first to do glycogenolysis
- GCs catabolize muscle and fat to use in gluconeogenesis
- GH stimulates lipolysis to increase glucose
What are the 4 main effects of GCs on carb and protein metabolism?
- stimuate gluconeogenesis and protein catabolism
- reduce peripheral glucose uptake
- increases expression of PEPCK in the liver promoting gluconeogenesis
- glycogen synthesis - only anabolic effect is increasing glycogen synthase
What is the effect of GCs on fat?
- increase the amount of lipolytic enzymes and stimulate FA release from adipocytes
- catecholamines increase enzyme activity
If there is GC excess, it will result in fat redistribution [moon face, buffalo hump]
What are the effects of glucocorticoids on muscle?
Low conc = muscle weakness
High conc = muscle wasting due to net nitrogen balance from protein catabolism
What are the 4 main effects of glucocorticoids on the immune system?
- effects on immune cell traffic
- lymphocytopenia and monocytopenia due to transient distribution of cells from vascular space into spleen, nodes, marrow
3 prevent neutrophil adherence to endothelium at inflammatory site increasing circulating count [demargination]
- inhibit chemotactic factors preventing macrophages from migrating to the site of injury
What is hydrocortisone?
A natural cortisol agonist that acts on MR and GR
What is prednisolone?
synthetic GC 5x more potent than cortisol
What is prednisone?
When is it not used?
Why is it used to treat pregnant women?
a prodrug converted to prendnisolone by 11b-HSD1 in the liver to become activated.
This is the most widely prescribed GC, but can’t be used with hepatic disease.
It is used to treat pregnant women because the fetal liver does not fully function and any active prednisolone can get converted back to prednisone
What is cortisone?
A prodrug that needs to be converted in the liver by 11b-HSD1 to cortisol
What are dexamethasone and triamcinolone?
potent GCs [20x > than cortisol] with minimal MR capabilities.
Triamcinolone is the topical version, but can cause muscle weakness
What is fludrocortisone?
What does it treat?
synthetic MC [aldosterone is the natural MC agonist]
It treats primary adrenal insufficiency in combo with hydrocortisone.
What are eplerenone/spironolactone used to treat?
- hypertension esp. due to MC excess or CHF
2. hirsutism because it antagonizes androgen receptor and progesterone receptor
What are the 2 actions of naturally occuring corticosteroids?
- GR effects - carb metabolism, anti-inflammatory, suppression of the immune system
- MR effects - sodium retention
What are the 2 synthetic compound with NO MC effects?
What are situations when you would want to use this?
- dexamethasone
- triamcinolone
You would use them when you want to avoid hypertension or other MC effects.
DEX- cancer, severe allergic rxns, cerebral edema
How are most corticosteroids delivered?
What if you desire rapid effects?
Prolonged effects?
localized effects?
Usually they are given orally [esp. prednisone and cortisone that need 11b-HSD1 from the liver].
Rapid - IV
Prolonged- IM
Localized - aerosol or topical
What are 4 causes of Addisonian crisis [acute adrenal insufficiency]?
- withdrawal of GC in patients with Addison’s
- withdrawal of corticosteroids after iatrogenic suppression of the HPA
- genetic diseases [CAH]
- hypovolemic shock with adrenal injury
What are the main symptoms of acute adrenal insufficiency?
- hyponatremia
- hyperkalemia
- hypoglycemia
- hypotension
[GI stress, weakness, lethargy, increased pigmentation,nausea]
You take a patient history and note:
- hypotension
- hypoglycemia
- hyponatremia
What do you assume this is until proven otherwise?
What will lab values show?
Adrenal insufficiency
Cortisol -low
ACTH- high
What is treatment for acute adrenal insufficiency?
- VOLUME
- STRESS DOSE [glucocorticoids]
sometimes, glucose or salt will be needed, but usually IV fluid and hydrocortisone is sufficient
What are causes of chronic primary adrenal insufficiency?
- adrenal gland destruction from autoimmune disease
- TB, AIDS
- adrenoleukodystrophy
A patient presents with depression, irritability and weight loss. They have hyponatremia and hyperkalemia. They are slightly low volume. Their skin is pigmented. What is the suspected problem and what is treatment?
Chronic primary adrenal insufficiency
Treat:
- salt
- hydrocortisone
- fludrocortisone
What is the cause of secondary adrenal insufficiency?
What are the symptoms?
What is treatment?
Secondary adrenal insufficiency is caused by defect in the HP axis [often iatrogenic]/
Symptoms: insidious onset of hyperkalemia, hyponatremia, hypotension, hypoglycemia without increased pigmentation or elevated ACTH
Treatment:
1. hydrocortisone
What are 8 non-endocrine diseases that utilize corticosteroids as palliative treatment?
- anti-inflammatory
- edema
- immunosuppression
- Inf. Diseases
- ocular disease
- cancer
- rashes
- diagnostic testing
When are corticosteroids used to treat rheumatoid arthritis?
Which drugs are used?
Prednisone in normal cases and triamcinolone in acute cases are used in progressive disease when salicylates, NSAIDs, antibody therapy and physical therapy have failed
What 5 conditions utilize corticosteroids as anti-inflammatory?
- RA
- osteoarthritis
- allergic disease
- asthma
- rheumatic disorders
In severe cases of hay fever, contact dermatitis, serum sickness, drug reactions and bee stings, what steroid can be given IV?
methyl-Prednisolone
What corticosteroids are used to treat asthma? When are they added to the regimen?
Flutacasone is added to the asthma regimen when B2-agonists alone has failed.
It is a metered dose, inhaled steroid.
Severe asthma attacks require parenteral administration of methyl-prednisolone
What corticosteroid is used for SLE and rheumatic vasculitis?
Prednisone
What corticosteroid is used to treat cerebral edema form global ischemic injury or tumors?
Dexamethasone- because it will help reduce the inflammation/edema without raising the BP
What corticosteroid is used before organ transplant, and for glomerulonephritis, collagen diseas and autoimmune disease?
Prednisone
What 3 infectious diseases are treated with corticosteroids?
- pneumocystis pneumonia in AIDS
- H. flu meningitis
- pneumococcal meningitis
What are the topical and systemic treatment for ocular disease?
Topical - dexamethasone
Systemic - predisone
What are the contraindications of corticosteroids?
- reduces bodies ability to combat all types of infections
2. reactivation and worsening of TB because it prevents granuloma formation
What are the direct side effects of prolonged corticosteroid therapy?
Hyperglycemia, hypertension, immunosuppression, myopathy, behavior disturbances, fat redistribution, osteoporosis, growth retardation
When the drug is stopped there will be HP axis suppression so —> Addison’s
